In the reflex control of the blood vessels the sympathetic neuro-effector process plays a major role. However the release of transmitter can be influenced by certain naturally occurring vasoactive agents such as acetylcholine and histamine, and by certain drugs. In some circumstances these agents may determine the magnitude of the reflex vascular response. A systematic study of such substances is proposed to determine the mechanism of their effect, to compare the dose required to elicit a neuronal effect with the dose which stimulates the smooth muscle cells directly, and to examine the interaction between different vasoactive substances on adrenergic neurotransmission. The substances to be studied will include histamine, 5-hydroxytryptamine, norepinephrine, prostaglandin, bradykinin, vasopressin, adrenal corticosteroids and acetylstrophanthidin. There is little or no sympathetic tone in the resistance vessels of exercising muscles. A possible explanation is that local changes such as release of adenosine or prostaglandins, alterations in pH, PCO2 and PO2, acting singly or in combination may depress the release of transmitter. This will be the subject of investigation. Cardiopulmonary receptors subserved by vagal afferents recently have been shown to exert a tonic inhibition of the vasomotor center. Key questions to be resolved are the characteristics of the receptors involved, their fiber type(s) and their contribution to the control of blood pressure in the conscious animal. The experiments will include direct recordings from vagal afferents in open and closed-chest animals, with changes in cardiac preload and afterload; analysis of anodal block to see if this technique will permit a differentiation between the medullated and nonmedullated vagal afferents; studies in trained conscious dogs to see if the cardiopulmonary receptors influence systemic arterial resistance in conjunction with the arterial baroreceptors, or only when the influence of the latter is diminished, or only when the cardiac volume is increased. The final experiments are directed toward estimating the metabolic cost of the cardiac sympathetic innervation.